Strategies for the reduction of inflammation and its effectiveness in preventing atherosclerosis and its complications are a current issue in cardiovascular research. Among the drugs aimed at modulating the atherothrombotic inflammatory process, colchicine is a unique, sophisticated anti-inflammatory agent, used since ancient times for the treatment of gout and familial Mediterranean fever, and more recently in the treatment of recurrent pericarditis and atrial fibrillation after cardiac surgery.Recent studies have evaluated the role of colchicine in the treatment of chronic coronary syndrome, acute coronary syndrome, and restenosis in patients treated with percutaneous coronary intervention, with encouraging results. (1)
CANTOS Trial (Canakinumab Anti-inflammatory Thrombosis Outcome Study) was the first study to demonstrate the benefit of an anti-inflammatory drug in the secondary prevention of coronary artery disease. This stimulated old and new research in this field will be taken up again. [i],(2)
Studies with colchicine in this field date back more than 30 years, I comment on the most interesting.(1)
The results of this study (Colchicine Treatment for the Prevention of Bare-Metal Stent Restenosis in Diabetic Patients) were presented in 2013. colchicine was associated with a lower rate of in-stent restenosis (16% vs. 33%, P < 0.01) and a similar trend was reported in a sub-analysis of the COLCOT trial. [ii],(3,6)
The low-dose colchicine (LoDoCo) was presented in 2013, included 532 patients with chronic coronary syndrome. Patients who received 0.5 mg daily had a significant reduction of composite CV events in comparison to the placebo group (5.3% vs. 16%). [iii],(4)
In 2020, the LoDoCo2 trial included a greater number of patients (5522) from Australia and the Netherlands, they were randomized to either colchicine 0.5mg daily or placebo. The primary endpoint was a composite of cardiovascular death, spontaneous myocardial infarction, ischaemic stroke, or ischemia-driven coronary revascularization. Over 90% of patients enrolled proved tolerant to colchicine and were randomized into the trial. At a median follow-up of 29 months, colchicine significantly reduced the primary endpoint compared with the placebo group (HR 0.69, 95% CI 0.57–0.83; P < 0.001) without significant side effects. [iv],(5)
The only trial sufficiently powered to assess the clinical effects of colchicine following an ACS was the Colchicine Cardiovascular Outcomes Trial (COLCOT) A total of 4745 patients were enrolled. Patients with a recent (<1month) myocardial infarction were randomized to colchicine 0.5mg daily or placebo and followed up for 4 years. Patients assigned to colchicine had a lower incidence of the composite of CV death, cardiac arrest, myocardial infarction, stroke, or urgent hospitalizations for angina (5.5% vs. 7.1%; HR 0.77, 95% CI 0.61–0.96). The outcome was mainly driven by a reduction in the incidence of stroke and urgent revascularization for angina. A sub-study of COLCOT suggested that the treatment effect was more marked when colchicine was initiated within 3 days of the onset of myocardial infarction (HR 0.52, 95% CI 0.32–0.84); however, the major benefits were accrued well after hospital discharge. In contrast to the LoDoCo2 trial, colchicine use was associated with a low but increased incidence of hospitalization for (non-fatal) pneumonia (0.9% vs. 0.4%, P= 0.03). [v],(6)
To date, four independent randomized controlled trials—LoDoCo, LoDoCo2, COLCOT, and COPS—evaluating the effect of colchicine in a broad spectrum of >11 000 patients with acute and chronic coronary disease followed for up to 5 years, demonstrated that colchicine may reduce the risk of CV death, myocardial infarction, ischaemic stroke and ischemia-driven revascularization by >30% (RR 0.63, 95% CI 0.49–0.81). [vi],(7)
The role of inflammation is unquestionable and is directly related to mortality, so we must always take it into account and treat it appropriately. That a drug as cheap as colchicine can have benefits in our patients, especially diabetics and cardiovascular diseases, is of great interest, so we must follow the results of more studies shortly.
[i] Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for atherosclerotic disease. N Engl J Med 2017; 377:1119–1113.
[ii]Deftereos S, Giannopoulos G, Raisakis K, Kossyvakis C, Kaoukis A, Panagopoulou V, Driva M, Hahalis G, Pyrgakis V, Alexopoulos D, Manolis AS, Stefanadis C, Cleman MW. Colchicine treatment for the prevention of bare-metal stent restenosis in diabetic patients. J Am Coll Cardiol. 2013 Apr 23;61(16):1679-85. doi: 10.1016/j.jacc.2013.01.055. Epub 2013 Apr 2. PMID: 23500260.
[iii] Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013 Jan 29;61(4):404-410. doi: 10.1016/j.jacc.2012.10.027. Epub 2012 Dec 19. PMID: 23265346.
[iv] Nidorf SM, Fiolet ATL, Eikelboom JW, Schut A, Opstal TSJ, Bax WA, Budgeon CA, Tijssen JGP, Mosterd A, Cornel JH, Thompson PL; LoDoCo2 Investigators. The effect of low-dose colchicine in patients with stable coronary artery disease: The LoDoCo2 trial rationale, design, and baseline characteristics. Am Heart J. 2019 Dec;218:46-56. doi: 10.1016/j.ahj.2019.09.011. Epub 2019 Oct 20. PMID: 31706144.
[v] Bouabdallaoui N, Tardif J-C, Waters DD, Pinto FJ, Maggioni AP, Diaz R, Berry C, Koenig W, Lopez-Sendon J, Gamra H, Kiwan GS, Blondeau L, Orfanos A, Ibrahim R, Gre´goire JC, Dube´ M-P, Samuel M, Morel O, Lim P, Bertrand OF, Kouz S, Guertin M-C, L’Allier PL, Roubille F. Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J 2020; 41:4092–4099.
[vi] Massimo Imazio, Mark Nidorf, Colchicine and the heart, European Heart Journal, 2021;, ehab221, https://doi.org/10.1093/eurheartj/ehab221.
DR. PITER MARTINEZ BENITEZ
